ES2338782T3 - ORAL PHARMACEUTICAL COMPOSITION THAT INCLUDES 15-HYDROXITESTOSTERONE AND DERIVATIVES. - Google Patents

Abstract

The invention relates to pharmaceutical dosage units for oral, transmucosal or transdermal administration containing 15- or 16-substituted testosterone analogues, as well as to therapeutic methods that employ these testosterone analogues. More particularly, the invention is concerned with such pharmaceutical dosage units containing at least 10 μg of an androgenic steroid selected from the group consisting of 15-hydroxytestosterones, 16-hydroxytestosterones, precursors thereof and mixtures of these hydroxytestosterones and/or their precursors; and a pharmaceutically acceptable excipient. The term “15-hydroxytestosterones” encompasses both 15α-hydroxytestosterone (15α, 17β-dihydroxy-4-androsten-3-one) and 15β-hydroxytestosterone (15β, 17β-dihydroxy-4-androsten-3-one). Similarly, the term “16-hydroxytestosterones” encompasses both 16α-hydroxytestosterone hydroxytestosterone (16α, 17β-dihydroxy-4-androsten-3-one) and 16β-hydroxytestosterone (16β, 17β-dihydroxy-4-androsten-3-one). The androgenic steroids according to the invention are advantageously employed in e.g. a method of treating or preventing androgen deficiency or a method of hormonal contraception.

Description

Oral pharmaceutical composition comprising 15-hydroxytestosterone and derivatives.

Technical field

The present invention is part of the field of Steroid chemistry. More particularly, it refers to pharmaceutical dosage units containing analogs of 15 or 16-substituted testosterone, as well as a therapeutic methods that employ these testosterone analogues. The testosterone analogs of the invention possess activity Androgenic

Background of the invention

British patent GB-B 774,064 refers to a process for the production of testosterones 15-substituted, particularly 15-hydroxytestosterone. Therapeutic applications of These substances are not mentioned anywhere in the patent.

French patent application FR-A 2 035 786 describes veterinary applications of 16α-? D-glucosiden of 16α, 17 dihydroxysteroid. It is stated that these steroids can be used as estrogens to prevent ovulation in animals such as rodents, dogs, cows and sheep. The claim 3 mentions the glycoside of 16α-hydroxytestosterone. Only the parenteral administration is mentioned in the application French

WO international patent application 01/23405 refers to a variety of steroid compounds and their use for the treatment of prostate cancer, hyperplasia of Benign prostate, breast cancer, alopecia, acne, hypogonadism and hirsutism Hydroxytestosterones are not mentioned.

Currently, the main therapeutic use of androgenic steroids is in the treatment of men hypogonadal Androgen deficiency treatment methods that comprise the administration of androgens, such as testosterone, dihydrotestosterone, dehydroepiandrosterone and various esters of testosterone, or derivatives and analogs such as mesterolone are known in the art.

Normally three types of androgen deficiency in males, that is, androgen deficiency primary (testicular insufficiency), androgen deficiency secondary (hypothalamic-hypophyseal insufficiency) and Androgen deficiency in elderly men (ADAM), also known as "male menopause" or "andropause."

Regarding the long-term administration of androgens in men, a distinction can be made between therapy and supplementation Therapy typically requires relatively dose highs that are normally similar to the production level of endogenous androgens. Supplementation, however, is adequate when carried out with dosages that are below the production level of endogenous androgens (i.e. testosterone, dihydrotestosterone and dehydropiandrosterone).

Due to concerns about the effects undesirable side effects, androgens are used sparingly both in therapy and hormone supplementation. In fact, Androgens are normally used only for male therapy humans when primary androgen deficiency has been diagnosed or high school.

Only a few androgens, p. ex. Dehydroepiandrosterone (DHEA) and 17α-alkylated testosterone derivatives are suitable for oral administration because, unlike testosterone, they are very resistant to liver metabolism. However, the disadvantages of oral administration are associated with the malabsorption of these androgens and their relatively high effect on the liver and in particular on the metabolism of the liver (Bhasin et al . (1997) J. Clin. Endocr. Metab. 82: 3-8). This is why, in existing protocols, androgens are generally administered in the form of 2-3 weekly depot injections or implants.

It has also been suggested in the prior art use a combination of a progestogen and an androgen in one method of male contraception. In such a method the progestogen is administer in an amount high enough to stop spermatogenesis - which leads to azoospermia and androgen is co-administrator to prevent androgen deficiency, which of otherwise it would cause the administration of the progestogen. Because concerns about reliability and possible effects side effects of the androgenic component, especially when administered orally, male contraceptives have not yet reached beyond the experimental stage.

Other therapeutic uses of androgens that have been proposed in the state of the art include the treatment of drug-induced lipodystrophy and wear syndrome retroviral in HIV-infected people, the improvement of recovery of critically ill catabolic people, treatment of benign gynecological diseases, hormonal contraceptives in women, delayed puberty, conversion of women into male.

As follows from the above, there is a unmet need for androgens that (i) can be used effectively in the aforementioned therapeutic methods without causing undesirable side effects, (ii) produce a very impact constant, that is predictable, and / or (iii) can be managed in a practical way, especially orally.

Summary of the Invention

The inventors have discovered in a way unexpected than steroids that have not been used in therapeutic applications, i.e. 15-hydroxy or 16-hydroxy substituted testosterone analogues, They meet the above requirements.

Surprisingly, it was discovered that analogs of hydroxytestosterone, according to the present invention, combine the adequate androgenic potency with acceptable oral bioavailability and the minimum impact on liver metabolism. In consecuense, the androgens present are particularly suitable for any therapeutic applications for which androgens They have been used or recommended. Analogs of hydroxytestosterone present can also be administered effectively, particularly at relatively low dosages such as those normally required by women, for transmucosal or transdermal administration.

Another advantage of hydroxitesterone analogues according to the invention is its predictable and constant therapeutic impact, which is believed to be related to absorption efficiency, its low hepatic effect and / or its low affinity for globulin binding of sex hormones (SHBG). Instead, the therapeutic effect of known androgens that are sometimes administered orally, mostly DHEA or 17α-alkylated derivatives of testosterone, depends largely on a physiology individual and even his / her diet. Consequently, these Androgens are usually applied in relatively high doses to ensure that the minimum effective dose is reached in each individual. Naturally, such high dosages have the disadvantage that lead to a relative overdose in some individuals, which in turn are likely to produce effects pronounced secondary.

Detailed description of the invention

Therefore, one aspect of the invention is refers to a pharmaceutical dosage unit for the transmucosal or transdermal oral administration containing minus 10 µg of an androgenic steroid selected from the group which consists of 15 hydroxytestosterones, 16 hydroxytestosterones, precursors thereof and mixtures of these hydroxytestosterones and / or its precursors; and a pharmaceutically excipient acceptable.

The term "15-hydroxytestosterones" comprises both 15α-hydroxytestosterone (15?, 17? -Dihydroxy-4-androsten-3-one) and 15? -hydroxytestosterone (15β, 17β-dihydroxy-4-androsten-3-one). Similarly, the term "16 hydroxytestosterones" It comprises both 16? hydroxytestosterone hydroxytestosterone (16?, 17? -Dihydroxy-4-androsten-3-one) and 16? -hydroxytestosterone (16?, 17? -Dihydroxy-4-androsten-3-one).

The term "precursor" used throughout the document refers to substances that become one of the hydroxytestosterones of the invention following administration of said precursor in a human subject.

Preferred steroid precursors androgens according to the present invention are derived from hydroxytestosterones present where the hydrogen atom of at less a hydroxyl group has been substituted by an acyl radical of a hydrocarbon, sulfonic or sulfamic carboxylic acid of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranal; or a straight chain glycosidic residue or branched containing 1-20 glycosidic units by residue

The hydroxytestosterones of the present invention have been shown to occur in mammals, which means that they offer the important advantage that they can be labeled as natural (Yamazaki et al . Arch Biochem Biophys 1997 Oct 1,346 (1): 161-9). In addition, as can be derived from the aforementioned article, both 15? -Hydroxytestosterone, 15? -Hydroxytestosterone and 16? -Hydroxytestosterone occur in the human body, which means that, prima facie , the risk of unwanted side effects is then lower than in the case of synthetic androgens or natural androgens that are not found in the human body. Thus, in a particularly preferred embodiment of the present invention, the androgenic steroid is selected from the group consisting of 15α-hydroxytestosterone, 15β-hydroxytestosterone, 16β-hydroxytestosterone, precursors thereof and mixtures thereof hydroxytestosterones and / or their precursors. Even more preferably, the androgenic steroid, is selected from the group consisting of 15? -Hydroxytestosterone, 15? -Hydroxytestosterone precursors thereof and mixtures of these hydroxytestosterones and / or their precursors.

The oral dosage units present they can be prepared according to any known method for technique of producing pharmaceutical compositions and Units of this type may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. Said dosage units may suitably contain a pharmaceutically acceptable non-toxic excipient. In case of p. ex. tablets, these excipients can be, for example, diluents inert, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; spraying agents and disintegrants, such as corn starch, or alginic acid; binding agents, such as starch, gelatin or acacia; Y lubricating agents, such as magnesium stearate, stearic acid or talcum powder The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action for a longer period. For example, a time delay material such as glyceryl monostearate or Glyceryl distearate can be used alone or with a wax.

Examples of dosage unit forms that can be administered orally include tablets, capsules of soft gelatin, including solutions used in soft gelatin, in aqueous capsule or oil suspensions, emulsions, pills, pills, tablets, syrups, elixirs and the like. Formulations For oral use they can also be presented as capsules of hard gelatin where the active substance is mixed with a diluent inert solid, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the component of spheroid is mixed with water or medium oil, such as peanut, liquid paraffin or olive oil. In a form of particularly preferred embodiment, the dosage units Oral according to the present invention are provided in the form of solids or semi-solid dosage units, especially in the form of tablets, capsules, wafers, pills, pills, powders or granules

The aqueous suspensions according to the invention contain the steroids in a mixture with the excipients suitable for the production of aqueous suspensions. Excipients of this type include a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic, and dispersing or humidifying agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an ethylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain of aliphatic alcohol (e.g., heptadecaethylene oxyethanol ), a product of the condensation of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived of fatty acid and an anhydrous hexitol (eg, polyoxyethylene sorbitan mono-oleate). The aqueous suspension may also contain one or more preservatives such as ethanol or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Ophthalmic formulations, as are known in the art, will be adjusted for pressure.
osmotic

Oil suspensions can be formulated to suspend the spheroid component in a vegetable oil, such like peanut oil, olive oil, sesame oil or oil of coconut, or in a mineral oil such as liquid paraffin. The oil suspensions may contain a thickening agent, such such as beeswax, hard paraffin or cetyl alcohol. Agents Sweeteners can be added to provide a preparation Tasty oral. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

The dispersible powders and granules of the invention, suitable for the preparation of an aqueous suspension by adding water they can be formulated from steroid component in a mixture with a dispersing agent, suspended and / or humectant, and one or more preservatives. The agents of suitable dispersion or humectants and suspending agents are exemplified by those described above. Additional Excipients, for example sweeteners, flavorings and coloring agents, They may also be present.

The pharmaceutical dosage unit of the invention may also be in the form of oil emulsions in Water. The oil phase may be a vegetable oil, such as olive or peanut oil, a mineral oil, such as paraffin liquid, or a mixture of these. Suitable emulsifying agents they include natural gums, such as acacia gum and tragacanth gum, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydride, such as sorbitan mono-oleate, and condensation products of these partial esters with oxide ethylene, such as polyoxyethylene polyoxyethylene sorbitan mono-oleate The emulsion may also contain sweeteners and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Formulations of this type may also contain an emollient, a preservative, flavoring or coloring agent.

The steroids of the present invention also can be administered in the form of suppositories for rectal or vaginal administration of the drug. These units of Dosage can be prepared by mixing the steroids with a suitable non-irritating excipient that is solid to normal temperatures but liquid at rectal temperatures and therefore, it is based on the rectum for drug release. Materials of this type are cocoa butter and glycols of polyethylene.

The current dosage unit contains preferably at least 20 µg, more preferably at least 40 \ mug and most preferably at least 60 \ steroid Androgenic In the case where the dosing unit has for object to provide a sustained release of steroids androgenic, p. ex. in case of a transdermal patch, the amount of androgenic steroid contained in the dosage unit It can be up to 1000 mg. Preferably, the amount of androgenic steroid does not exceed 500 mg, more preferably than exceeds 200 mg Most preferably, the amount of Androgenic steroid in the dosage unit does not exceed 100 mg

In an embodiment particularly preferred of the invention, the dosage unit is designed For oral administration. Examples of dosage units oral that can be used properly to deliver Current steroids include tablets, capsules, wafers, dragees, pills, powders or granules.

Normally, the present dosage unit Oral pharmaceutical has a weight in the range of 0.1-10 grams The amount of androgenic steroid contained in the unit of the oral dosage is preferably at least 30 µg, more preferably at least 50 µg and most preferably at least 80 \ mug. Normally the amount of steroid contained in the oral dosage unit it will not exceed 50 mg, more preferably it will not exceed 30 mg, most preferably not will exceed 20 mg.

The hydroxytestosterone analogues of the The present invention can be advantageously employed in a method of male contraception. As mentioned here before, such a method requires the combined administration of a progestogen and An androgen Normally the amount of progestogen included in the Dosage unit present will exceed 10 \ mug, preferably it will exceed 30 µg. In one embodiment particularly preferred, the dosage unit present it also contains a progestogen in an equivalent amount between 75 and 800 \ mug, more preferably between 100 and 500 \ mug levonorgestrel.

In other applications, p. ex. in therapy hormonal replacement in women or contraception in women, may it is advantageous to administer the present analogues of hydroxytestosterone in combination with an estrogen. By consequently, the dosage unit present, in addition to the Androgenic steroid present, may properly contain a estrogen, preferably in an amount of at least 10 µg, more preferably in an amount of at least 15 µg.

Examples of progestogens that can be employed in the dosage unit present as well as the methods described herein include progesterone, levonorgestrel, norgestimate, norethisterone, didrogesterone, drospirenone, 3-beta-hydroxidesogestrel, 3-keto desogestrel (= etonogestrel), 17 deacetyl norgestimate, 19-norprogesterone, acetoxypropanenolone, allilesthrenol, anagestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, etisterone, ethinodiol diacetate, flurogestone acetate, gastrinone, steroetinonetin, hydroxythrenes, steroxetone, steroxetone, steroxetone, steroxetone, steroxetone, steroxetone, steroxetone, steroxetone, steroxetone, steroxetone, steroxytenedone , medrogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone (= norethisterone), noretinodrel, norgestrel (includes d-norgestrel and dl-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17alfa-17-methylene-17-methyl-11 -19-norpregna-4,15-diene-20-yn-3-one, tibolone, trimegestone, algestone acetophenide, nestorone, promegestone, 17-hydroxyprogesterone esters, 19 nor-17-hydroxyprogesterone, 17alpha-ethynyl-testosterone, 17alpha-ethynyl-19-nor-testosterone, d-17beta-acetoxy-13beta-ethyl-17alfa-ethinyl-gon-4-en- 3-one oxime, precursors of these compounds that are capable of releasing these progestogens in vivo when used in the present method and combinations thereof. Preferably the progestogen is selected from the group consisting of progesterone, desogestrel, etonogestrel, signodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, didrogesterone, precursors of these progestogens and combinations thereof.

Examples of estrogens that can be suitably used in accordance with the present invention include ethinyl estradiol, mestranol, quinestranol, estradiol, estrone, estrano, estriol, estetrol, equine conjugated estrogens, their precursors that are capable of releasing such estrogen in vivo when used in the Present method and its combinations. Preferably the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, estetrol and combinations thereof.

Preferred steroid precursors androgens according to the present invention are derived from hydroxytestosterones present in which the hydrogen atom of at least one hydroxyl group has been substituted by an acyl radical of a carboxylic, sulfonic or sulfamic hydrocarbon acid of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranal; or a straight chain glycosidic residue or branched containing 1-20 glycosidic units by residue

Another aspect of the invention relates to a method of curative or prophylactic treatment of a mammal, said method comprising oral, transmucosal or transdermal to said mammal of the dosage unit Pharmaceutical present as described above. The term transmucosal administration as used in this case makes reference to intravaginal, intrauterine, rectal, intranasal, pulmonary, oral and sublingual delivery, the most preferred being intravaginal administration The present method is especially Suitable for the treatment of human beings.

The oral, rectal, intranasal administrations oral and pulmonary are ideal for the administration of (at least) once a day. Transdermal administration is advantageously applied at frequencies between once a day and once a month. Intravaginal and intrauterine administrations are advantageously applied at administration frequencies between once per week and once a month.

For reasons of convenience and also for achieve high adaptability rates, the present method uses preferably administration intervals of 1 day, 1 week or 1 month. Regimes that use oral administration once a day, transdermal administration once a week or the intravaginal administration once a month are particularly preferred. Most preferably the present method comprises At least one daily administration.

The androgenic steroid (s) of the invention are advantageously administered in a daily amount with an average of at least 0.5 µg per kg of body weight. Preferably, the average daily amount is at least 1 ? per kg body weight, more preferably at least 1.5 \ mug per kg of body weight. The average daily amount should not Normally exceed 1.5 mg per kg body weight. Preferably the average daily amount does not exceed 1 mg per kg body weight, more preferably does not exceed 0.5 mg per kg body weight

The method, according to the present invention, is preferably used in a method of treatment or prevention of androgen deficiency (in men or women); a method of hormonal contraception (in men or women); a method of treatment or prevention of wear syndrome, lipodystrophy induced by antiretroviral drug, lack of well-being or fatigue in people infected with HIV; a method of reversing the state catabolic caused by a chronic disease, intervention surgical, oncological condition, trauma and / or malnutrition; a method of treatment or prevention of leydig cell dysfunction and epithelial germ damage and damage after chemotherapy cytotoxic; a method of treatment or prevention of fatigue or weight maintenance, hemoglobin or neutrophil count during or after cytotoxic chemotherapy or radiotherapy; a method of treatment or prevention of gynecological disorders benign; a method to improve libido (in men or women); a method of treatment or prevention of delayed puberty; or a method of support in the conversion of women into men. As I know mentioned here, the administration of the present steroids is particularly advantageous when employed in a method of treatment and prevention of androgen deficiency, a method of hormonal contraception or a method of treatment or prevention of benign gynecological disorders. It is observed that the symptoms of Androgen deficiency can occur in both men and women. women. In a particularly preferred embodiment, the This is used to treat or prevent deficiency of androgens or is used as a contraceptive method in males

The aforementioned methods usually employ the continuous administration of the present steroids during a period of at least 10 days, preferably at least 20 days. In a particularly preferred embodiment, the present Steroids are given for a period of at least 100 days with intervals without administration that do not exceed 10 days, which preferably do not exceed 8 days.

In a preferred embodiment, the method present comprises the co-administration of a progestogen in a average daily amount of at least 0.2 µg per kg of weight body and / or an estrogen in an average daily amount of at minus 0.2 µg per kg body weight. Normally the average daily amount of co-administered progestogen or estrogen not exceed 1 mg per kg body weight, more preferably said amount shall not exceed 500 µg per kg of body weight, of the most preferable form will not exceed 300 µg per kg of weight bodily.

Still another aspect of the invention makes reference to the use of an androgenic steroid selected from the group that consists of 15-hydroxytestosterones, 16-hydroxytestosterones, precursors thereof and mixtures of these hydroxytestosterones and / or their precursors in the preparation of an oral, transmucosal or dosage unit transdermal as described in this document. In a form of particularly preferred embodiment, said androgenic steroid It is used in the preparation of a solid oral dosage unit or semi-solid, especially an oral dosage unit in form of pill, capsule, wafer, granules, pill, powder or granules

The invention is subsequently illustrated. by the following examples.

Examples

Example one

An established competitive binding trial of steroid was used to determine relative binding affinity of 15? -hydroxytestosterones (15?, 17? -Dihydroxy-4-androsten-3-one), 15β-hydroxytestosterone (15β, 17β-dihydroxy-4-androsten-3-one) and 16? -hydroxytestosterones (16?, 17? -Dihydroxy-4-androsten-3-one) to the androgen receptor (AR). Testosterone (17? -Hydroxy-4-androsten-3-one) and 5α-dihydroxytestosterones (DHT, 5α, 17β-dihydroxy-androsten-3-one) They served as controls in this trial.

The method used was adapted from the scientific literature and described in detail by Chang et al (1987, J. Steroid Biochem., 27, 1-3, 123-131). The rat AR recombinant was expressed and purified from E. Coli . In vitro assays involved the use of AR and [3 H] mibolerona, at a fixed concentration of 1.5 nM, as the labeled ligand. The recombinant AR was dissolved in a binding buffer (50 mM Tris-base, pH 7.5, 0.8 mM NaCl, 10% glycerol, 2 mM dithiothreitol, 1 mg / ml BSA and 2% ethanol) and aliquots of duplicate were then incubated with [3 H] mibolerone at a final concentration of 1.5 nM, together with an excipient (1.0% DMSO), or the same amount of excipient containing increasing concentrations of unlabeled spheroid ligands as competitors After incubation for 4 hours at 4 ° C, unbound ligands were removed and the amounts of [3 H] miboleron bound to the AR were measured. The average amounts of [3 H] miboleron bound to the AR in each concentration of competitors was used to make inhibition curves. IC50 values were subsequently determined by a nonlinear, least squares regression analysis. Inhibition constants (Ki) were calculated using the Cheng and Prusoff equation (Cheng et al ., 1973, Biochem. Pharmacol., 22, 3099-3108), using the measured IC50 of the compounds evaluated, the radioligand concentration used in the trial, and the historical values for the radioligand Kd, which has been established as 3 nM.

The average Ki values obtained for 15? -Hydroxytestosterone, 15? -Hydroxytestosterone, 16? -Hydroxytestosterone, testosterone and DHT from three separate experiments are shown in Table 1. For comparison of binding affinities, the Ki value of DHT (showing maximum affinity) was arbitrarily set at 100% and used to calculate relative affinities (table 1). Compared to DHT and testosterone, 15? -Hydroxytestosterone, 15? -Hydroxy-
Testosterone and 16? -hydroxytestosterone bind 2 to 3 orders of magnitude lower affinity with A (Table 1).

TABLE 1 Inhibition constants (Ki) experimentally determined for AR link of 15α-hydroxytestosterone, 15β-hydroxytestosterone, 16β-hydroxytestosterone, testosterone and 5α-dihydroxytestosterone (DHT). Affinity of Relative linkages are also shown, using the DHT Ki value at 100%

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one

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Example 2

To determine the in vivo androgenic strength of 15-substituted testosterone derivatives, 15? -Hydroxytestosterone (15?, 17? -Dihydroxy-4-androsten-3-one) and 15? -Hydroxytestosterone (15?, 17? -Dihydroxy-4-androsten-3-one) were administered orally, once a day, to immature male Wistar rats for 5 consecutive days. Testosterone (17? -Hydroxy-4-androsten-3-one) and 5? -Dihydroxystestosterone (DHT, 15?, 17? -Dihydroxy-androsten-3-one), both administered orally, served as positive controls In this biological test.

15α-hydroxytestosterone, 15β-hydroxytestosterone, testosterone and 5α-dihydroxytestosterone were dissolved in a 2% Tween 80 aqueous suspension, at the final test concentrations of 3 mg / ml and 1 mg / ml. Groups of 5 immature Wistan male rats, weighing 50 ± 2 grams, received either excipient treatment or were given 30 or 10 mg / kg / day test substance by oral forced feeding in a dosage volume of 10 ml per kg for 5 consecutive days. During the experiment, the animals were housed in cages of 45 X 23 X 15 cm and kept at a controlled temperature of 22-24 ° C and ambient humidity (60-80%) with cycles of 12 light / dark hours. Food (laboratory diet, rodent diet, PMI international nutrition) and water intake was ad libitum .

The animals were sacrificed 24 hours after receiving the final dose and the drained weight of the seminal vesicle of each animal was recorded and the average drained weight per group was calculated. The increase in the average drained weight of the seminal vesicle in relation to the average drained weight of the seminal vesicle of rats treated by excipient was considered indicative of androgenicity in vivo .

In vivo androgenicity data are shown in Table 2. Both 15α and 15β substituted analogs of testosterone hydroxy induced a dose-dependent increase and significant increase in the drained weight of the seminal vesicle. These in vivo androgenic effects were similar or equipotent to the dose-dependent effects observed for testosterone and considerably more potent than the in vivo androgenicity observed after oral administration of DHT, a classical androgen and the active testosterone metabolite in vivo (O 'Donnel et al ., 1996, Endocrinology, 137, 2703-2710).

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TABLE 2 Average drained weight gain of the gallbladder seminal in relation to the average drained weight of the excipient (2% Tween-80) treated animals for groups of 5 rats immature Wistan, treated once a day, orally, during five consecutive days with 15α-hydroxytestosterone, 15? -Hydroxytestosterone, testosterone or 5α-dihydroxytestosterone (DHT). Powers Relative androgenic are also shown, using DHT as reference (100%)

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2

Example 3

An established steroid bond assay competitive (Hammond and Lahteenmaki. 1983. Clin Chem Acta 132: 101-110) was used to determine the affinity of the relative bond of 15α-hydroxytestosterone (15α-OH-T), 15β-hydroxytestosterone (15? -OH-T), dehydropiandrosterone (DHEA, testosterone (T) and 5α-dihydrotestosterone (DHT) for Human sex hormone binding globulin (SHBG).

Human SHBG was purified from transgenic mouse serum, as previously described (Avvakumov GV et al ., 2000. J Biol Chem 275: 25920-25925). Human SHBG prepared in this way was evaluated as> 99% pure by polyacrylamide gel electrophoresis under denaturing conditions. Its spheroid binding characteristics are indistinguishable from SHBG in human serum (Avvakumov GV et al ., 2000. J Biol Chem 275: 25920-25925). The in vitro assay involved the use of purified human SHBG and [3 H] DHT as a labeled ligand. Human SHBG was treated for 30 minutes at room temperature with a suspension of dextran-coated carbon (DCC) in phosphate buffered saline (PBS) to remove any spheroid ligand. After centrifugation (2,000 X g for 10 min) to settle the DCC, the supernatant containing human SHBG was diluted in PBS at a concentration of 1 nM based on its spheroid binding capacity.

The duplicated aliquots (100 µl) of this human SHBG solution were then incubated in an equal volume at [3 H] DHT at 10 nM, together with 100 µl of PBS only or the same amount of PBS containing increasing concentrations of steroid ligands not labeled as competitors in tubes polystyrene test. After incubation for 1 hour at room temperature the reactions of the mixtures were placed in an ice bath for another 15 min. Aliquots (600 µl) of a cold suspension like DCC ice was then added to each tube, and after a brief mixture of 2 seconds, was incubated each tube in an ice bath for 10 min. The ligands do not linked absorbed into DCC were then removed by centrifugation (2,000 X g for 15 min at 4 ° C), and the amounts of [3 H] labeled DHT linked to SHBG were counted in 2 ml ACS scintillation cocktail used in spectrophotometer liquid scintillation The average amount of [<3> H] DHT tagging linked to the SHBG at each competitor concentration (B) was expressed as a percentage of average amounts of DHT [3 H] labeled linked to SHBG in the absence of competitors (T), and were set against the competitor concentration in each test tube.

3

Figure 1: Competition curves showing displacement of [3 H] DHT from human SHGB using 5α-dihydrotestosterone (DHT), testosterone (T), dehydroepiandrosterone (DHEA), 15α-dihydroxytestosterone (15α-OH-T), 15β-dihydroxytestosterone (15?-OT-T) as competitors. The results are expressed as link (B) cpm on each cpm link of concentration / total competitor (T) cpm in the absence of competitor as a percentage.

The results of the link tests competitive are represented in figure 1. The data show that 15α-OH-T and 15? -OH-T does not bind SHBG human, when compared to DHT, T or DHEA in a binding assay competitive in which [3 H] DHT was used as a ligand labelled. Consequently, unlike other androgens, the binding of 15α-OH-T or 15? -OH-T to human SHBG It can be considered negligible.

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References cited in the description This list of references cited by the applicant has been collected exclusively for reader information. Do not It is part of the European patent document. It has been made with the greatest diligence; the EPO however does not assume any responsibility for possible errors or omissions Patent documents cited in the description

GB 774064 B [0002]

FR 2035786 A [0003]

WO 0123405 A [0004]

Non-patent bibliography cited in the description

Bhasin et al . J. Clin. Endocr Metab ., 1997 , vol. 82, 3-8 [0009]

Yamazaki et al . Arch Biochem Biophys , 01 October 1997, vol. 346 (1), 161-9 [0020]

Chang et al . J. Steroid Biochem ., 1987 , vol. 27 (1-3), 123-131 [0047]

Cheng et al . Biochem Pharmacol ., 1973 , vol. 22, 3099-3108 [0047]

O'Donnel et al . Endocrinology , 1996 , vol. 137, 2703-2710 [0052]

Hammond ; Lahteenmaki Clin Chem Acta , 1983 , vol. 132, 101-110 [0053]

Avvakumov GV et al . J Biol Chem , 2000 , vol. 275, 25920-25925 [0054]

Claims (13)

1. A pharmaceutical dosage unit in form of a tablet, a capsule, a wafer, a dragee, a pill, powders or granules, which contain at least 10 µg of a androgenic steroid selected from the group consisting of 15-hydroxytestosterones, precursors thereof and mixtures of these hydroxytestosterones and / or their precursors; and a pharmaceutically acceptable excipient, said precursors being derivatives of hydroxytestosterones where the hydrogen atom of at least one hydroxyl group has been substituted by a radical of acyl of a carboxylic, sulfonic or sulfamic hydrocarbon acid of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranal; or a linear or branched glycosidic chain of residues containing 1-20 glycosidic units per residue. 2. Pharmaceutical dosage unit according claim 1, wherein the steroid is selected from the group consisting of 15? -hydroxytestosterone, precursors thereof and mixtures of 15α-hydroxytestosterone and / or these precursors 3. The pharmaceutical dosage unit according to claim 1, wherein the steroid is selected from the group consisting of 15? -hydroxytestosterone, precursors thereof and mixtures of 15β-hydroxytestosterone and / or its precursors 4. Pharmaceutical dosage unit according to any of claims 1-39, wherein the Dosing unit contains between 20 µg and 1000 mg of androgenic steroid. 5. Pharmaceutical dosage unit according to the claim 4 wherein the dosage unit contains between 40 and 500 mg of the androgenic steroid. 6. Pharmaceutical dosage unit of according to any of claims 1-5, where the dosage unit additionally contains at least 10 \ mug of a progestogen and / or at least 10 \ mug of a estrogen 7. Androgenic steroid for use in a method of curative or prophylactic treatment of a mammal, said method comprising oral steroid administration androgenic, said androgenic steroid being selected from the group consisting of 15-hydroxytestosterones, precursors thereof and mixtures of these hydroxytestosterones and / or its precursors, and a pharmaceutically acceptable excipient, being said precursors derived from hydroxytestosterones where the hydrogen atom of at least one hydroxyl group has been substituted by an acyl radical of a hydrocarbon acid carboxylic, sulfonic or sulfamic of 1-25 atoms of carbon; tetrahydrofuranyl; tetrahydropyranal; or a chain linear or branched glycosidic residue containing 1-20 glycosidic units per residue. 8. Androgenic steroid according to claim 7 where the steroid is selected from the group consisting of 15α-hydroxytestosterone, precursors of same and mixtures of 15α-hydroxytestosterone and / or these precursors. 9. Androgenic steroid according to claim 7, where the steroid is selected from the group consisting of 15β-hydroxytestosterone, precursors thereof and mixtures of 15? -hydroxytestosterone and / or these precursors 10. Androgenic steroid according to any of claims 7-9, wherein the method comprises steroid administration in a daily average amount in the range of 0.5 µg to 1.5 mg per kg body weight, per kg of body weight. 11. Androgenic steroid according to claim 10, wherein the method comprises administration of the steroid in an average daily amount in the range of 1 \ mug at 1 mg per kg body weight. 12. Androgenic steroid according to anyone of claims 7-11 for use in a method of treatment and prevention of androgen deficiency; a hormonal contraception method; a method of treatment or wear syndrome prevention, lipodystrophy induced by antiretroviral drug, lack of well-being or fatigue in individuals HIV infected; as a way to reverse the catabolic state caused by a chronic disease, surgical intervention, oncological condition, trauma and / or malnutrition; a method of treatment or prevention of leydig cell dysfunction and damage epithelial germinal after cytotoxic chemotherapy; a method of treatment or prevention of fatigue or weight maintenance, hemoglobin or neutrophil count during or after cytotoxic chemotherapy or radiotherapy; a method of treatment or prevention of benign gynecological disorders; a method of improve libido; a method of treatment or prevention of puberty delayed or a support method in the conversion of women into man. 13. The androgenic steroid according to claim 12 for use in a treatment method or prevention of androgen deficiency or in a method of contraception hormonal in men.